Risperidone is a benzoisoxazole derivative developed by Janssen Pharmaceutical (Belgium) (see patent document 1). As pharmacological actions of risperidone, the anti-dopaminergic action, the anti-serotonergic action and the catalepsy inducing action have been confirmed. At present besides being widely used in clinical practice as an antischizophrenia drug, use in treatment for hyperphagia, a cosmetic composition for treatment of a sensitive skin and the like have been proposed (see Patent Documents 2 and 3).
It is considered that the effect of risperidone against schizophrenia is due to adjustment of the central nervous system mainly based on dopamine D2 receptor antagonistic action and serotonin 5-HT2 receptor antagonistic action. In addition, risperidone shows an excellent effect against positive symptoms such as hallucination and delusion as well as a strong effect against negative symptoms such as an emotional social withdrawal and a blunted affect, while it has characteristics that it shows relatively few side effects of the pyramidal tract (chill, stiffness, etc.) compared with a conventional typical antipsychotic agent, and therefore, it is considered to be an extremely useful antischizophrenia drug which can tremendously improve the QOL (quality of life) of patients.
As an administration method for risperidone, an oral administration method using tablets, fine granules, a liquid preparation for internal use has been used. However, the oral administration has some drawbacks such as susceptibility to a first-pass effect in the liver after absorption of the drug and an observation of a temporary and unnecessary high blood concentration after the administration. In addition, in the oral administration many side effects such as a gastrointestinal tract disorder, a vomiting feeling and a loss of appetite have been reported. Further, in schizophrenia patients, it is said that actually about 75% of them have difficulties to take an oral preparation regularly. Therefore, with the aim of solving such problems in the oral administration and making a preparation which patients can easily take with safety and persistence, administration methods using patches have been examined in recent years. An administration method using a patch can dissolve the above various problems in oral administration methods and has advantages such as reduction of administration frequency, improvement in compliance, and easiness of administration and discontinuation, therefore, it has been expected as an useful administration method.
However, because, in the horny layer, keratin-containing cells and an intercellular lipid are laminated in layers, permeability of a drug is generally extremely low, and in addition to this, because the horny layer of a normal skin has a barrier function to prevent invasion of foreign substances into the body, only blending risperidone in an adhesive layer composition of the conventional patch could not give a risperidone-containing patch having a sufficient skin absorbability.
Therefore, to increase the skin absorbability of risperidone in a percutaneous administration method using a patch, a patch containing a skin permeation enhancer such as fatty acids or solvent such as propylene glycol together with risperidone has been proposed (see patent document 4). However, even with these attempts, the skin absorbability of risperidone blended in a patch is not sufficient, and actually, a patch containing risperidone has not yet been on the market. Therefore, development of a preparation, which has an excellent percutaneous absorbability and sustainability to the possible extent for therapeutic use, has been desired.
On the other hand, in a percutaneous absorption preparation containing a basic drug, it was already proposed that a skin permeability of the basic drug was improved by blending an organic acid salt or an organic acid with the basic drug (see patent documents 5-7). However, in these documents, although hypnotic-sedative agents, psychotropic agents and the like are exemplified as the basic drugs, there was no suggestion whether a drug-containing patch could actually be prepared as an effective preparation having a sufficient skin absorbability to the possible extent for therapeutic use for patients. In addition, an external preparation whose skin absorbability was enhanced by formation of an ionic liquid between an ionic drug and a substance to be an counter ion was already proposed (see patent document 8); as ionic drugs, only indomethacin, diclofenac sodium, sodium cromoglycate, tramadol hydrochloride and piroxicam were exemplified. Further, the literature described that the melting point of the ionic liquid, which was prepared with indomethacin or diclofenac sodium as the ionic drug and lidocaine or lidocaine hydrochloride as a substance to be the counter ion, lowered. However, the lowering of basic drugs is not specifically disclosed since both indomethacin and diclofenac are acid drugs. Additionaly, although an ointment containing indomethacin or diclofenac sodium as the ionic drug and being blended with lidocaine or lidocaine hydrochloride as a substance to be the counter ion is disclosed, there is no suggestion in any way whether a patch containing such ionic liquid of the drug can achieve a sufficient skin absorbability and sustainability.
Patent document 1: JP, B, 6-13511
Patent document 2: JP, A, 2003-525865
Patent document 3: JP, A, 2001-511782
Patent document 4: JP, A, 11-503138
Patent document 5: JP, A, 11-302161
Patent document 6: WO00/61120
Patent document 7: WO01/007018
Patent document 8: JP, A, 2005-82512